Mechanisms of Preferential Reinveration

描述(由申请者提供)：神经损伤每年损害超过8万美国人的功能。令人惊讶的是，神经损伤的治疗，即手术恢复粗大神经的连续性，在上个世纪几乎没有改变。促进神经再生的因素的发现刺激了各种动物模型的实验。然而，尽管这项工作前景看好，我们仍然缺乏关于哪些因素促进体内特定轴突群体再生的准确知识。这项建议扩展了我们实验室正在进行的工作，以提供这一知识。我们已经证明，曾经被认为表达单一表型的周围神经髓鞘雪旺细胞，其生长因子的表达有很大的差异。此外，这些特化的雪旺细胞优先支持其天然轴突群体的再生。我们现在建议确定哪些在感觉神经和运动神经中差异表达的因子负责选择性地促进感觉和运动轴突再生。分析将从不同类型移植物中生长因子浓度与其促进感觉或运动再生的能力的相关性开始。我们设计了一种新的体外神经修复技术，它与体内修复非常相似，并将用来观察增强或消除特定因子功能的效果。然后，雪旺细胞将在体内进行修饰，通过将慢病毒载体导入它们或用DNA质粒电穿孔来增加有希望的因子的表达。最有效的生长因子将通过测量它们对神经移植后模式和自主功能恢复的影响来评估在大鼠正中神经中的作用。确定最佳感觉和运动轴突再生所需的特定因素将对神经修复、神经移植和使用雪旺细胞促进脊髓再生具有直接和直接的临床意义。公共卫生意义一个多世纪以来，皮神经移植一直被用于神经重建，但效果往往很差。我们最近的工作表明，皮肤神经和肌肉神经在其生长因子的产生方面存在显著差异，并支持特定形态的再生。拟议的实验将确定哪些生长因素对这种特异性负责，并将制定策略，利用这些因素来改善神经修复和重建的结果，可能每年帮助数千名患者。

DESCRIPTION (provided by applicant): Nerve injury compromises the function of over 80,000 Americans each year. Surprisingly, the treatment of nerve injury, surgical restoration of gross nerve continuity, has changed little in the last century. The discovery of factors that promote nerve regeneration has stimulated experimentation in a variety of animal models. In spite of this promising work, however, we still lack precise knowledge of which factors promote the regeneration of specific axon populations in vivo. This proposal extends work ongoing in our laboratory to provide this knowledge. We have shown that Schwann cells of myelinating peripheral nerve, once thought to express a single phenotype, vary widely in their growth factor expression. Furthermore, these specialized Schwann cells preferentially support the regeneration of their native axon population. We now propose to determine which of the factors expressed differentially in sensory and motor nerve are responsible for selective promotion of sensory and motor axon regeneration. Analysis will begin with correlation of growth factor concentration in various types of graft with their ability to promote sensory or motor regeneration. We have devised a novel technique of nerve repair in vitro that closely mimics repair in vivo, and will use this to observe the effects of augmenting or eliminating the function of specific factors. Schwann cells will then be modified in vivo to increase the expression of promising factors by transfecting them with lentiviral vectors or electroporating them with DNA plasmids. The most effective growth factors will be evaluated in the rat median nerve by measuring their impact on recovery of patterned and voluntary function after nerve grafting. Identification of the specific factors needed for optimal sensory and motor axon regeneration will have direct and immediate clinical implications for nerve repair, nerve grafting, and the use of Schwann cells to promote spinal cord regeneration. PUBLIC HEALTH RELEVANCE For over a century graft of cutaneous nerve has been used for neural reconstruction, often with poor results. Our recent work has shown that cutaneous and muscle nerves differ significantly in their growth factor production, and support regeneration on a modality-specific basis. The proposed experiments will determine which growth factors are responsible for this specificity, and will devise strategies for using these factors to improve the outcome of nerve repair and reconstruction, potentially helping thousands of patients a year.